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Largest-Ever Search for Autism Genes Reveals New Clues

Molecular model of DNA

The largest search for autism genes to date has implicated components of the brain's glutamate chemical messenger system and a previously overlooked site on chromosome 11. The new study is the first to emerge from the Autism Genome Project Consortium, a public-private collaboration involving more than 120 scientists and 50 institutions in l9 countries.

The Autism Genome Project Consortium, supported in part by NIH, pursues studies to identify specific genes and gene variants that contribute to autism spectrum disorders (ASD). One of its goals is to understand how candidate genes might work in the brain to produce ASD. Researchers are exploring the interactions between suspect genes as well as between genes and environmental factors.

The current analysis, which was funded by several NIH Institutes and other organizations, was based on 1,168 families with at least two members affected by ASD. The researchers analyzed the participants' DNA using microarrays made by Affymetrix, Inc. that enabled them to detect more than 10,000 single nucleotide polymorphisms (SNPs) at once. SNPs are minute variations in DNA. The researchers used the massive amount of data they generated to reveal SNPs that might be linked to ASD.

The researchers also developed a way to analyze "submicroscopic" variations in DNA — the doubling, tripling or further multiplying of stretches of genetic material. The number of copies of particular stretches of DNA someone has, they reasoned, may also factor in their susceptibility to ASD. Since each major autism candidate gene likely contributes to risk for a relatively small percentage of families, key links to ASD can easily be lost in the statistical noise generated by submicroscopic variations, just as a high level of static can drown out a weak radio signal. With their massive analysis, the researchers were able to filter through this noise.

The researchers reported in the online edition of Nature Genetics on February 18, 2007, that components of the brain's glutamate neurotransmitter system are likely linked to ASD. Glutamate is used by nerve cells in the brain to communicate. It also plays an important role in wiring up the brain during early development. Some key genes associated with the glutamate system are located in chromosome regions that were previously linked with autism. For example, strongly tied to autism was a previously suspected site on chromosome 11 that harbors genes for proteins that remove excess glutamate from the space between nerve cells.

The researchers found a number of submicroscopic variations in suspect chromosomal locations. They propose that multiple gene variants, interacting with each other and with submicroscopic variations, contribute to ASD.

As more genes involved with ASD are identified, studies of how they work in the brain will help to sort out the genetic and environmental influences on ASD. A second phase of Autism Genome Project studies will follow up on the leads suggested in this first phase.